更新于：2024-11-01

Protein kinase N (PKN) family x PKC

更新于：2024-11-01

基本信息

关联

项与 Protein kinase N (PKN) family x PKC 相关的药物

AD-288

靶点

PKC

作用机制

PKC抑制剂 [+1]

在研机构-

原研机构

Anthra Pharmaceuticals, Inc.

在研适应症-

非在研适应症

肺癌

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Protein kinase N (PKN) family x PKC 相关的临床结果

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100 项与 Protein kinase N (PKN) family x PKC 相关的转化医学

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0 项与 Protein kinase N (PKN) family x PKC 相关的专利（医药）

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131

项与 Protein kinase N (PKN) family x PKC 相关的文献（医药）

2024-07-01·Journal of Biological Chemistry

Molecular Insights into the Regulatory Landscape of Protein Kinase C-Related Kinase-2 (PRK2/PKN2) Using Targeted Small Compounds

Article

作者: Winkel, Angelika F ; Gross, Lissy Z F ; Engel, Matthias ; Biondi, Ricardo M ; Galceran, Facundo ; Cämmerer, Simon ; Schulze, Jörg O ; Zeuzem, Stefan ; Fröhner, Wolfgang ; Leroux, Alejandro E

The PKC-related kinases (PRKs, also termed PKNs) are important in cell migration, cancer, hepatitis C infection, and nutrient sensing. They belong to a group of protein kinases called AGC kinases that share common features like a C-terminal extension to the catalytic domain comprising a hydrophobic motif. PRKs are regulated by N-terminal domains, a pseudosubstrate sequence, Rho-binding domains, and a C2 domain involved in inhibition and dimerization, while Rho and lipids are activators. We investigated the allosteric regulation of PRK2 and its interaction with its upstream kinase PDK1 using a chemical biology approach. We confirmed the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF)-mediated docking interaction of PRK2 with PDK1 and showed that this interaction can be modulated allosterically. We showed that the polypeptide PIFtide and a small compound binding to the PIF-pocket of PRK2 were allosteric activators, by displacing the pseudosubstrate PKL region from the active site. In addition, a small compound binding to the PIF-pocket allosterically inhibited the catalytic activity of PRK2. Together, we confirmed the docking interaction and allostery between PRK2 and PDK1 and described an allosteric communication between the PIF-pocket and the active site of PRK2, both modulating the conformation of the ATP-binding site and the pseudosubstrate PKL-binding site. Our study highlights the allosteric modulation of the activity and the conformation of PRK2 in addition to the existence of at least two different complexes between PRK2 and its upstream kinase PDK1. Finally, the study highlights the potential for developing allosteric drugs to modulate PRK2 kinase conformations and catalytic activity.

2024-03-19·Biochemistry

Lipid-Binding Regions within PKC-Related Serine/Threonine Protein Kinase N1 (PKN1) Required for Its Regulation

Article

作者: Lin, Jason L. J. ; Yuan, Hanna S.

PKC-related serine/threonine protein kinase N1 (PKN1) is a protease/lipid-activated protein kinase that acts downstream of the RhoA and Rac1 pathways. PKN1 comprises unique regulatory, hinge region, and PKC homologous catalytic domains. The regulatory domain harbors two homologous regions, i.e., HR1 and C2-like. HR1 consists of three heptad repeats (HR1a, HR1b, and HR1c), with PKN1-(HR1a) hosting an amphipathic high-affinity cardiolipin-binding site for phospholipid interactions. Cardiolipin and C18:1 oleic acid are the most potent lipid activators of PKN1. PKN1-(C2) contains a pseudosubstrate sequence overlapping that of C20:4 arachidonic acid. However, the cardiolipin-binding site(s) within PKN1-(C2) and the respective binding properties remain unclear. Herein, we reveal (i) that the primary PKN1-(C2) sequence contains conserved amphipathic cardiolipin-binding motif(s); (ii) that trimeric PKN1-(C2) predominantly adopts a β-stranded conformation; (iii) that two distinct types of cardiolipin (or phosphatidic acid) binding occur, with the hydrophobic component playing a key role at higher salt levels; (iv) the multiplicity of C18 fatty acid binding to PKN1-(C2); and (v) the relevance of our lipid-binding parameters for PKN1-(C2) in terms of kinetic parameters previously determined for the full-length PKN1 enzyme. Thus, our discoveries create opportunities to design specific mammalian cell inhibitors that disrupt the localization of membrane-associated PKN1 signaling molecules.

2023-11-01·Cell Reports Medicine

High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

Article

作者: Kim, Daehwan ; Stevenson, Erica ; Faraji, Farhoud ; Saddawi-Konefka, Robert ; Thomas, Craig J ; Arang, Nadia ; Coma, Silvia ; Swaney, Danielle L ; Wang, Zhiyong ; Alessi, Dario R ; Aplin, Andrew E ; Krogan, Nevan J ; Gutkind, J Silvio ; Ramirez, Sydney I ; Rigiracciolo, Damiano C ; Lubrano, Simone ; Molinolo, Alfredo A ; Pachter, Jonathan A ; Yang, Jing ; Tosto, Frances A ; Ceribelli, Michele ; Zhou, Yuan ; Bogomolovas, Julius

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.